tbuckley/cabot-search huggingface dataset:
Abstract 2316: Automating ctDNA liquid biopsy workflow for mutation testing: From sample extraction to dPCR analysis utilizing the Maxprep™ Liquid Handler, Maxwell® extraction system, and high-plex detection assays
Authors: Michael Granitsiotis, Kimberly Gutierrez, Doug Horejsh, Monica Yue
Journal: Cancer Research (2023)

Abstract Liquid biopsies are a minimally-invasive sampling approach to overcome the heterogeneity of tumors and represent a valuable source of circulating tumor DNA (ctDNA) for oncological biomarker analysis. The use of ctDNA as a surrogate for tissue DNA is increasingly popular, and advances in the detection and characterization of ctDNA has enabled liquid biopsy assay integration into clinical utilization. However, an innate challenge with measurement of ctDNA is the requirement for highly sensitive quantitation to reliably detect rare genetic aberrations. Digital PCR has emerged as a powerful technology addressing the needs for next-generation analysis of liquid biopsies samples. Having reliable assays for analysis of key oncology targets help drive adoption of this technology into real-world applications. The exquisite sensitivity of digital PCR requires sample preparation methods that reduce variation, making automation of any manual steps highly desirable. Automation also provides flexibility to scale up as testing volumes increase while simultaneously decreasing overall complexity for the operator. Here we present an automated workflow for ctDNA extraction and analysis using the Maxprep™ Liquid Handler, Maxwell® extraction system (Promega Corporation), and a new, high-throughput digital PCR consumable, the Ruby Chip (Stilla Technologies). This ultra-sensitive detection for liquid biopsy samples was performed using a high-plex dPCR assay. Citation Format: Michael Granitsiotis, Kimberly Gutierrez, Doug Horejsh, Monica Yue. Automating ctDNA liquid biopsy workflow for mutation testing: From sample extraction to dPCR analysis utilizing the Maxprep™ Liquid Handler, Maxwell® extraction system, and high-plex detection assays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2316.
Abstract 3012: Increased lung cancer risk and associated risk factors in tuberculosis survivors: a Korean population-based study
Authors: Dong Won Park, Seong Mi Moon, Hayoung Choi, Sang Hyuk Kim, Hyung Koo Kang, Jin Hyung Jung, Kyungdo Han, Dong Wook Shin, Hyun Lee
Journal: Cancer Research (2023)

Abstract Background: Although studies have suggested an association between previous tuberculosis (TB) infection and increased lung cancer risk, there are limited data comprehensively evaluating the effects of smoking and chronic obstructive pulmonary disease (COPD) on the association. Methods: This population-based cohort study enrolled TB survivors (n=75,467) ≥20 years of age between 2010-2017 and 1:1 age- and sex-matched controls (n=75,467). Subjects were followed for one year after the date of TB diagnosis to the date of the incidental lung cancer, death, or December 2018. Results: During a median follow-up duration of 4.8 (interquartile range, 2.9-6.6) years, the incident lung cancer risk was 1.71-fold (95% confidence interval [CI], 1.49-1.97) higher in TB survivors than in the controls. Compared to never-smoker, non-TB infected controls, TB survivors who were current smokers with ≥20 pack-years showed the highest risk of lung cancer (adjusted hazard ratio [aHR], 6.78; 95% CI, 5.26-8.74). In terms of COPD, the risk of lung cancer was higher in TB survivors with COPD compared to non-COPD, non-TB-infected controls (aHR, 2.43; 95% CI, 2.03-2.91). However, smoking as well as COPD did not have significant interaction on the association between TB and lung cancer development (p for interaction&amp;gt;0.05 for both). Risk factors related to incident lung cancer among TB survivors were pulmonary TB, age &amp;gt;60 years, smoking, and the presence of COPD or asthma. Conclusions: Previous TB infection is an independent risk factor for lung cancer without significant interaction with smoking status or amount and COPD. Citation Format: Dong Won Park, Seong Mi Moon, Hayoung Choi, Sang Hyuk Kim, Hyung Koo Kang, Jin Hyung Jung, Kyungdo Han, Dong Wook Shin, Hyun Lee. Increased lung cancer risk and associated risk factors in tuberculosis survivors: a Korean population-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3012.
Abstract 3014: Association between HLA-KIR allele interaction combinations and density of T-cell subsets in colorectal cancer
Authors: Claire Elizabeth Thomas, Jeroen Huyghe, Tomotaka Ugai, Hang Yin, Yasutoshi Takashima, Daniel D. Buchanan, Conghui Qu, Li Hsu, Andressa Dias Costa, Stephen Gallinger, Robert Grant, Sushma Thomas, Shuji Ogino, Amanda I. Phipps, Jonathan Nowak, Ulrike Peters
Journal: Cancer Research (2023)

Abstract Background: Germline genetic factors central to immunity, such as human leukocyte antigen (HLA) variants, have been associated with several immune-related phenotypes such as response to immune checkpoint inhibitors. However, HLA and killer-cell immunoglobulin-like (KIR) gene combinations, which may modulate immune function, have not been studied in relation to T-cell density in cancer. Methods: This study was conducted within 3 well characterized epidemiologic studies that collected colorectal tumor tissue blocks (N=484). We profiled the in-situ T cell landscape of CRC using digital imaging, machine learning, and a customized 9-plex multiplexed immunofluorescence panel with antibodies directed against CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, and MKI67. HLA and KIR variants were imputed from genome-wide array datasets through SNP2HLA and KIR*IMP methods. We used multivariable ordinal logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between HLA-KIR activation/inhibition ligand combinations with quartile of T cell densities in CRC adjusting for age, sex, GWAS panel, and the first two principal components of ancestry. Results: Presence of KIR2DL2+HLAC1+ and KIR2DS2+HLAC1+ combinations were associated with lower odds of greater CD3+CD8+ T-cell density quartile, however these findings were not statistically significant [OR = 0.73, 95% CI (0.52, 1.02), p-value = 0.067; OR = 0.74 95% CI (0.53, 1.04), p-value= 0.082, respectively]. There was no association between HLA-KIR combinations and CD3+CD4+ T-cell density quartile. Further results will examine HLA and KIR genes individually, as well as additional combination variables and more specific T-cell density subsets. Conclusions: Further investigation is needed to determine if germline genetics related to immune profile plays a role in T-cell densities in CRC. Citation Format: Claire Elizabeth Thomas, Jeroen Huyghe, Tomotaka Ugai, Hang Yin, Yasutoshi Takashima, Daniel D. Buchanan, Conghui Qu, Li Hsu, Andressa Dias Costa, Stephen Gallinger, Robert Grant, Sushma Thomas, Shuji Ogino, Amanda I. Phipps, Jonathan Nowak, Ulrike Peters. Association between HLA-KIR allele interaction combinations and density of T-cell subsets in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3014.
Abstract 2843: RN486, a Bruton’s tyrosine kinase inhibitor, reverses multidrug resistance in ABCG2-overexpressing cancer cells
Authors: Xing-Duo Dong, Qisi Lu, Yi-Dong Li, Qiu-Xu Teng, Zi-Ning Lei, Zhe-Sheng Chen
Journal: Cancer Research (2023)

Abstract Overcoming ATP-binding cassette subfamily G member 2 (ABCG2)-mediated multidrug resistance (MDR) has attracted the attention of scientists because one of the critical factors leading to MDR is the overexpression of ABCG2. Identification of novel chemotherapeutic reagents as inhibitors of ABCG2 has been considered an effective strategy. RN486, a Bruton’s Tyrosine Kinase (BTK) inhibitor, was discovered to potentially reverse ABCB1-mediated MDR. In this study, we reported that RN486 effectively antagonizes ABCG2-mediated MDR in cancer cells. Non-toxic concentrations of RN486 remarkably increased the sensitivity of ABCG2-overexpressing cancer cells to conventional anticancer drugs mitoxantrone and topotecan. The reversal mechanistic studies showed that RN486 increased the accumulation and decreased the efflux of ABCG2 substrate drug in ABCG2-overexpressing cancer cells. In addition, the inhibitory effect of RN486 on ABCG2-associated ATPase activity was also verified. Docking analysis indicated a strong binding between RN486 and ABCG2 transporter. Meanwhile, the AGCG2 subcellular localization and expression level were not altered by the treatment of RN486. Taken together, our studies suggest that RN486 can antagonize ABCG2-mediated MDR in cancer cells via interacting with ABCG2 and inhibiting the transporting function. RN486 could be potentially used in combination with chemotherapy against ABCG2-mediated MDR in cancers. Citation Format: Xing-Duo Dong, Qisi Lu, Yi-Dong Li, Qiu-Xu Teng, Zi-Ning Lei, Zhe-Sheng Chen. RN486, a Bruton’s tyrosine kinase inhibitor, reverses multidrug resistance in ABCG2-overexpressing cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2843.
Abstract 3133: Loss of the Y chromosome as a candidate driver in solid tumors
Authors: Meifang Qi, Esther Rheinbay, Andrew A. Lane, Jiali Pang, Irene Mitsiades
Journal: Cancer Research (2023)

Abstract It has long been recognized that certain cancer types afflict female and male patients disproportionately. The reasons for this disparity include differences in male and female physiology, effect of sex hormones, risk behavior and environmental exposures, and different copy number of the sex chromosomes X and Y. Loss of Y (LOY) is common in peripheral blood cells in aging men, and this phenomenon is associated with several diseases. However, the frequency and role of LOY in tumors is little understood. Here, we present a comprehensive catalog of LOY in about 5,000 primary tumors from male patients in the TCGA. We show that LOY rates vary by tumor type, and provide evidence for LOY being either a passenger or driver event depending on context. LOY in uveal melanoma specifically is associated with age, survival and is an independent predictor of poor outcome. LOY creates common dependencies on DDX3X and EIF1AX in male cell lines, suggesting that LOY generates unique vulnerabilities that could be therapeutically exploited. Citation Format: Meifang Qi, Esther Rheinbay, Andrew A. Lane, Jiali Pang, Irene Mitsiades. Loss of the Y chromosome as a candidate driver in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3133.
Abstract 2339: Exploration of multiple immunotherapy modalities in ostesarcoma
Authors: Aliaa A. Ismail, Daniel J. Patton, Theresa A. Higgins, Maninder Sandey, Bruce F. Smith, Payal Agarwal
Journal: Cancer Research (2023)

Abstract Osteosarcoma (OS) is the most common primary bone malignancy affecting long bones in children and the third most frequent in adults in the United States. It is highly invasive and metastatic. The survival rates over the last 20 years are unchanged. Therefore, it is essential to develop novel, targeted therapeutic approaches to treat OS. In pursuit of that goal, novel models are needed. Due to the high similarity in cancer genetics, the spontaneous occurrence of tumors, and the presence of an intact immune system, dogs are deemed an excellent cancer immunotherapy model. OS is also the most common malignant bone tumor (80%) in dogs. Monotherapies like oncolytic viruses and immune checkpoint inhibitors have been shown to be insufficient for effective cancer treatment. Therefore, we propose a combination of immune checkpoint inhibition and oncolytic virotherapy to target osteosarcoma tumor cells. In this combined therapy, the oncolytic virus will serve to both stimulate an inflammatory response and transmit the checkpoint inhibitor, which in turn will block PD-1-directed down-regulation of T cells, allowing the adaptive immune system to respond better to tumors. In order to evaluate this approach in the canine model, we have developed an oncolytic virus (CAV2-AU-M2) based on canine adenovirus type 2 and armed with an immune checkpoint inhibitor, an anti-canine PD1 single domain camelid antibody (sdAb). Four canine osteosarcoma cell lines, D17, D22, MCKOS, and CF11, were cultured in two-dimensional (2D) and three-dimensional (3D) cultures and were infected with CAV2-AU-M2 to analyze the infective and lytic effects of the virus. CAV2-AU-M2 infected and lysed the cells in 2D. The virus also produced anti-PD1 sdAb upon infecting the cells. Similarly, results were evident in 3D cultures. The virus infected the spheroids in the outer layers on Day 4 and slowly diffused towards the core in 7 days. The spheroids infected started showing some cell death on day 4, which progressed significantly by Day 7. This approach to oncolytic virotherapy makes the tumor more visible to the immune system and abrogates tumor-induced immune suppression. Citation Format: Aliaa A. Ismail, Daniel J. Patton, Theresa A. Higgins, Maninder Sandey, Bruce F. Smith, Payal Agarwal. Exploration of multiple immunotherapy modalities in ostesarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2339.
Abstract 4764: The therapeutic potential of lnc-<i>HLX-2-7</i> in group 3 medulloblastomas in children
Authors: Keisuke Katsushima, Bongyong Lee, Menglang Yuan, Stacie Stapleton, George Jallo, Sudipta Seal, Charles G. Eberhart, Ranjan J. Perera
Journal: Cancer Research (2023)

Abstract Medulloblastoma (MB) is an aggressive brain tumor that predominantly affects children. Recent high-throughput sequencing studies suggest that the non-coding RNA genome, in particular long non-coding RNAs (lncRNAs), contributes to MB formation and tumor progression. Here we report the identification of a novel lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 MBs. In this study, we report that lnc-HLX-2-7 RNA specifically accumulates in the HLX (host gene of lnc-HLX-2-7) promoter region and activates HLX expression by recruiting multiple factors including enhancer elements. RNA sequencing and chromatin immunoprecipitation revealed that HLX directly binds to the promoters of several tumor-promoting genes, including MYC, and activates their expression. Furthermore, intravenous treatment with antisense oligonucleotides targeting lnc-HLX-2-7 coated with cerium-oxide nanoparticle (CNP-lnc-HLX-2-7) reduced tumor growth (40-50%) in intracranial MB xenograft mouse model (n=10, p&amp;lt;0.01, t-test). We found that the combinatorial therapy of CNP-lnc-HLX-2-7 and cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared to CNP-lnc-HLX-2-7 monotherapy (n=10, p&amp;lt;0.01, t-test) only. We report here the importance of the lnc-HLX-2-7-HLX-MYC axis in regulating group 3 MB progression and provide a strong rationale for using lnc-HLX-2-7 as a specific and potent therapeutic target for the group 3 MBs in children. Citation Format: Keisuke Katsushima, Bongyong Lee, Menglang Yuan, Stacie Stapleton, George Jallo, Sudipta Seal, Charles G. Eberhart, Ranjan J. Perera. The therapeutic potential of lnc-HLX-2-7 in group 3 medulloblastomas in children. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4764.
Abstract 3119: A novel tissue resident memory T cell (TRM) signature predicts prognosis and tumor microenvironment of patients with melanoma
Authors: Chongming Jiang, Jianrong Li, Elena Helman, Xiling Shen, Chao Cheng
Journal: Cancer Research (2023)

Abstract Background: Melanoma is a prime example of how basic and translational research can improve cancer prognosis The tumor immune microenvironment (TIME) of melanoma is a dynamic, heterogeneous mixture of multiple immune cells and malignant and nonmalignant cells. Tissue resident memory T cells (TRM) may be prognostic for improved melanoma survival and proliferate during treatment with immune checkpoint inhibitors. The role of TRM in melanoma and rare melanoma subtypes is unknown. Method: Our goal was to examine the relationship between TRM abundance and melanoma prognosis. We generated TRM signatures using multiple independent single-cell RNA sequencing data from human melanoma cells to infer TRM abundance. Lastly, we built a LASSO Cox regression model that predicts patient survival. The TCGA dataset was used as a test group. Model accuracy was validated using Kaplan-Meier survival analysis, receiver operating characteristic curves, principal component analysis, and t-distributed stochastic neighbor embedding. Findings: We found a significantly longer overall survival in patients with high TRM infiltration. Furthermore, we found that TRM can interact with the tumor microenvironment and genomic features of melanoma, making TRM abundance positively correlate with the prognosis of melanoma patients. Melanoma abundance was also significantly associated with several common genomic aberrations, including the TP53 mutation. In addition, we developed a 20-gene risk score that significantly classifies patients into low- and high-risk categories. We found that in several independent datasets, patients with high risk scores had significantly worse overall survival than patients with low risk scores. Conclusions: Altogether, our findings suggest that TRM abundance may positively correlate with melanoma survival. We developed a high-precision LASSO Cox regression model based on the new TRM abundance characteristics. Our study shows that this model effectively predicts the prognosis of melanoma patients and may provide new therapeutic targets and measure the effectiveness of melanoma-directed therapies. Keywords: Tissue resident memory T cell, tumor immune microenvironment, melanoma, prognosis Citation Format: Chongming Jiang, Jianrong Li, Elena Helman, Xiling Shen, Chao Cheng. A novel tissue resident memory T cell (TRM) signature predicts prognosis and tumor microenvironment of patients with melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3119.
Abstract 6184: Pre-clinical study of SYX3759, a novel PARG inhibitor for the treatment of homologous recombination deficient malignancies
Authors: Xuzhen Tang, Yaqi Cui, Lanqiao Zhang, Huihui Jin, Zeqiong Xu, Hu He, Chongxun Ge, Song Liu, Xiaochun Yu, Song Shi
Journal: Cancer Research (2023)

Abstract Although PARP inhibitors (PARPi) are very successful on the treatment of BRCA-mutant cancer, the tumor spectrum targeted by PARPi is quite narrow. Interestingly, Poly(ADP-ribose) Glycohydrolase (aka PARG), the major dePARylation enzyme, has emerged as a promising therapeutic target for cancer treatment. Here, we have developed a cell membrane permeable PARG inhibitor with subnanomolar IC50. SYX3759 directly binds to the catalytic domain of PARG and induces significant accumulation of PARylation at DNA lesions, where it traps numerous DNA repair factors, such as XRCC1. Compared to PARPi, such as Olaparib, SYX3759 shows selective and potent cytotoxicity on a broader spectrum of homologous recombination deficient (HRD) tumors both in vitro and in vivo. Moreover, SYX3759 is well tolerated at the highest dose tested without obvious adverse effect on hematopoiesis. Collectively, SYX3759 is a potent PARG inhibitor both in vitro and in vivo warranting future clinical trials for the treatment of HRD cancers and beyond. Citation Format: Xuzhen Tang, Yaqi Cui, Lanqiao Zhang, Huihui Jin, Zeqiong Xu, Hu He, Chongxun Ge, Song Liu, Xiaochun Yu, Song Shi. Pre-clinical study of SYX3759, a novel PARG inhibitor for the treatment of homologous recombination deficient malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6184.
Abstract 4672: <i>In-vivo</i> tumor implantation site exhibits differential immune response in solid tumors
Authors: Rajeev Shrimali, Jasmine Borroel, Carmen Sunico, Bridget Corcoran, Bianca Carapia, Rowan Prendergast, Jantzen Sperry, Jonathan Nakashima
Journal: Cancer Research (2023)

Abstract Successful discovery and development of cancer targeted therapeutics depends on testing these agents in the clinically most relevant translational models. Emerging evidence highlights the importance of the local tumor microenvironment in evaluating the efficacy of new therapeutics, especially for immunotherapies. Historically, patient-derived xenograft (PDX) modeling involves subcutaneous implantation which minimally represents the actual human tumor site. Here, we use PBMC humanized PDX models to demonstrate differences in the tumor microenvironment, overall immune response, and the pharmacological outcome, between subcutaneous and orthotopic PDX models. These findings highlight the importance of testing cancer therapeutics in the most physiologically relevant setting for greater translation into clinical success. Citation Format: Rajeev Shrimali, Jasmine Borroel, Carmen Sunico, Bridget Corcoran, Bianca Carapia, Rowan Prendergast, Jantzen Sperry, Jonathan Nakashima. In-vivo tumor implantation site exhibits differential immune response in solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4672.